Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma

Background: Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-avb3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-avb3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK)) and bi-cyclic RGD (E[c(RGDyK)]2) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. Principal Findings: Human glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-avb3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3,-8 and-9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3,-8 and-9 inhibitor presented significant protection against E[c(RGDyK)]2 peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-avb3 was correlated with the enhanced apoptosis in U87MG cells. Conclusions: This study provides a novel concept of targeting integrin-avb3 with RGD peptides in combination with low